Health Care Utilization and Costs After Initiating Budesonide/Formoterol Combination or Fluticasone/Salmeterol Combination Among COPD Patients New to ICS/LABA Treatment

BACKGROUND: Chronic obstructive pulmonary disease (COPD) affects approximately 15 million people in the United States and accounts for approximately $36 billion in economic burden, primarily due to medical costs. To address the increasing clinical and economic burden, the Global Initiative for Chronic Obstructive Lung Disease emphasizes the use of therapies that help prevent COPD exacerbations, including inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA). OBJECTIVE: To evaluate health care costs and utilization among COPD patients newly initiating ICS/LABA combination therapy with budesonide/formoterol (BFC) or fluticasone/salmeterol (FSC) in a managed care system. METHODS: COPD patients aged 40 years and older who initiated BFC (160/4.5 μg) or FSC (250/50 μg) treatment between March 1, 2009, and March 31, 2012, were identified using claims data from major U.S. health plans. BFC and FSC patients were propensity score matched (1:1) on age, sex, prior asthma diagnosis, prior COPD-related health care utilization, and respiratory medication use. COPD-related, pneumonia-related, and all-cause costs and utilization were analyzed during the 12-month follow-up period. Post-index costs were assessed with generalized linear models (GLMs) with gamma distribution. Health care utilization data were analyzed via logistic regression (any event vs. none) and GLMs with negative binomial distribution (number of visits) and were adjusted for the analogous pre-index variable as well as pre-index characteristics that remained imbalanced after matching. RESULTS: After matching, each cohort had 3,697 patients balanced on age (mean 64 years), sex (female 52% BFC and 54% FSC), asthma and other comorbid conditions, prior COPD-related health care utilization, and respiratory medication use. During the 12-month follow-up, COPD-related costs averaged $316 less for BFC versus FSC patients ($4,326 vs. $4,846; P = 0.003), reflecting lower inpatient ($966 vs. $1,202; P < 0.001), pharmacy ($1,482 vs. $1,609; P = 0.002), and outpatient/office ($1,378 vs. $1,436; P = 0.048) costs, but higher emergency department ($257 vs. $252; P = 0.033) costs. Pneumonia-related health care costs were also lower on average for BFC patients ($2,855 vs. $3,605; P < 0.001). Similarly, initiating BFC was associated with lower all-use health care costs versus initiating FSC ($21,580 vs. $24,483; P < 0.001, respectively). No differences in health care utilization were found between the 2 groups. CONCLUSIONS: In this study, although no difference was observed in rates of health care utilization, COPD patients initiating BFC treatment incurred lower average COPD-related, pneumonia-related, and all-cause costs versus FSC initiators, which was driven by cumulative differences in inpatient, outpatient, and pharmacy costs.

C hronic obstructive pulmonary disease (COPD) is an increasingly burdensome respiratory illness that affects about 6.5% of the adult population (approximately 15 million people) in the United States. [1][2][3][4][5] The disease is characterized by inflammation and declining lung function and is linked to increasing rates of morbidity and mortality. The severe effects of COPD are manifest in several aspects of patients' lives and activities: 700,000 inpatient hospitalizations, 10.3 million outpatient visits, and 1.5 million emergency department (ED) visits in 2010, 2,6 along with considerable absenteeism, in the United States. 7 COPD results in substantial economic burden ($36 billion), estimated at $32.1 billion for medical costs and $3.9 billion for worker absenteeism-about 16.4 million lost work days-in the United States in 2010. By 2020, annual COPD-related medical costs are projected to increase to $49 billion. 6 In the face of such serious economic and clinical challenges, the Global Initiative for Chronic Obstructive Lung Disease • Inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) therapies are common first-line treatment options for the treatment of chronic obstructive pulmonary disease (COPD) in patients with a history of exacerbations. • Prior research on the health care cost differences between the ICS/LABA therapies budesonide/formoterol (BFC) and fluticasone/salmeterol (FSC) in the United States is extremely limited.

What is already known about this subject
• This study adds to previous work analyzing differences in health care costs for patients initiating the 2 therapies by providing a longer follow-up period and the use of multivariable models to adjust for pre-index differences. • This study demonstrated that COPD patients initiating BFC therapy had lower COPD-related, pneumonia-related, and all-cause costs than patients initiating FSC treatment. • This study found no significant differences in health care utilization between patients initiating BFC therapy versus those initiating FSC therapy.
treatment index date was defined as the first date of treatment initiation corresponding to the first prescription fill of either BFC or FSC within the study intake period. All patients initiating BFC and FSC therapy between March 1, 2009, and March 31, 2012, were identified in HIRE. The HIRE contains enrollees in 14 major regional health plans and at the time of this study contained longitudinal claims data for more than 31 million enrollees from all U.S. census regions. This study was conducted in accordance with the Agency for Healthcare Research and Quality's guidelines for conducting comparative effectiveness research. 18 The management of all data and study materials conformed with all the relevant Health Insurance Portability and Accountability Act of 1996 (HIPAA) rules. A limited dataset, which excluded patient-identifying information, was used for all analyses, as defined by the HIPAA Privacy Rule. A national, independent institutional review board approved this study.
Inclusion/Exclusion Criteria. Only patients who were naïve to ICS/LABA during the 12 months prior to initiating BFC (160/4.5 μg) or FSC (250/50 μg) were included in the study. The pharmacy claim date of treatment initiation was considered the index date. To be included, patients were required to be aged at least 40 years on the index date and have continuous active health plan enrollment, with both medical and pharmacy benefits, encompassing at least 12 months before (pre-index period) and 12 months after (post-index period) the index date. Furthermore, at least 1 inpatient visit with a primary diagnosis for COPD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] diagnosis code 491.xx, 492.xx, or 496.xx), and/or at least 1 ED visit with a COPD diagnosis (either primary or secondary), and/or at least 2 other medical claims with a COPD diagnosis (either primary or secondary) during the pre-index period were required for inclusion in the study. Patients diagnosed with cancer, those who received ≥ 180 days of oral corticosteroids (OCS) in the 12-month pre-index period, and those who initiated both study medications on the same date were ineligible for the study.

Outcome Measures
Health Care Costs. The costs attributable to inpatient hospitalizations, ED visits, outpatient/office visits, skilled nursing facility visits, and pharmacy prescriptions were compiled and reported as COPD-related, pneumonia-related, and all-cause (due to any condition). The total cost of care, including actual costs paid by the patient and those paid by the health plan, were included in all cost calculations. The sum of all costs was considered the total health care cost, and the sum of all nonpharmacy costs was considered medical costs. COPD-related costs include the costs of events that were linked to a COPD diagnosis code as a primary diagnosis for inpatient stays and (GOLD) emphasized the use of therapies that help to prevent COPD exacerbations as a central element of its disease management recommendations. 8 The use of controller medications is supported by the GOLD 2015 treatment guidelines, which endorsed inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) combination therapies as a first-line maintenance therapy for patients with a history of COPD exacerbation. 8,9 At the time of this study, 2 ICS/LABA combination agents, budesonide/formoterol (BFC, 160/4.5 μg) 10 4,13,14 ; however, information on costs associated with these ICS/LABA combination treatments is limited. To our knowledge, only 1 U.S. study evaluated medical service costs for patients receiving BFC and FSC treatments. 4 The authors found no difference in mean total costs between the COPD patient groups receiving BFC and FSC agents.
To begin addressing this important evidence gap, we evaluated health care costs and utilization among COPD patients naïve to ICS/LABA fixed-dose combination medications who initiated BFC or FSC therapies in a large, real-world, managed care setting. To reduce the likelihood that a shorter follow-up time, as evidenced by a prior study, 4 might have contributed to the lack of observed difference in mean costs between BFC and FSC cohorts, this study used a longer follow-up time of 12 months. Furthermore, in recognition of pneumonia as an important safety endpoint and cost driver among patients receiving ICS/LABA combination therapy, this study also evaluated mean pneumonia-related costs for the 2 cohorts. 15,16 The cost outcomes analyzed in this study were a secondary endpoint in a study primarily designed to compare the rates of COPD exacerbations in the year following initiation of the study medications (ClinicalTrials.gov identifier NCT01921127). 17

■■ Methods Study Design and Population
In this retrospective, claims-based study, patients identified in the HealthCore Integrated Research Environment (HIRE) were followed for 12 months after initiating treatment with ICS/ LABA combination agents BFC (160/4.5 μg) or FSC (250/50 μg). The primary objective of this study was to examine differences in COPD exacerbation rates between the 2 groups, the results of which have been published elsewhere. 17 This analysis used the intent-to-treat approach and attributed all post-index treatment outcomes to the index medications of interest. The Health Care Utilization and Costs After Initiating Budesonide/Formoterol Combination or Fluticasone/Salmeterol Combination Among COPD Patients New to ICS/LABA Treatment any diagnosis for other services. A COPD-related pharmacy cost was defined as the cost of any of the following medications and medication classes, and includes the cost of the index drug: ICS/LABA, ICS, LABA, long-acting muscarinic antagonist (LAMA), short-acting beta2-agonist (SABA), short-acting muscarinic antagonist (SAMA), SABA/SAMA combination, OCS, theophylline, roflumilast, and antibiotics. Pneumonia-related costs did not require a primary pneumonia diagnosis and included visits with any pneumonia diagnosis (480.xx-486.xx), including viral, bacterial, and other/unspecified pneumonia. Pneumonia-related costs did not include any pharmacy costs, because of the inability to determine whether prescribed antibiotics (the typical medication received via a pharmacy for the treatment of pneumonia) were specific to pneumonia or for the treatment of another infection. All-cause health care costs include the costs of all health care encounters regardless of reason or diagnosis. For all cost data, the cost of procedures were included in their applicable place of service; for example, if a pulmonary function test was performed during a COPDrelated office visit, the cost of that test would be included in the COPD-related office visit costs.
Health Care Utilization. The presence of a visit (any vs. none) and the number of visits by place of service (inpatient hospitalization, intensive care unit [ICU], ED, outpatient/ office visit) were captured. As with cost calculations, health care utilization was considered COPD related if the medical claim contained an applicable COPD diagnosis code; a primary diagnosis was required for inpatient stays, and a claim in any position was adequate for other service locations. Pneumoniarelated utilizations included visits with a diagnosis of viral, bacterial, or other/unspecified pneumonia in any position. The diagnostic criteria using the claims database was validated against abstracted medical records with 80% positive predictive value. 19 Other Variables of Interest. Comorbid conditions were based on the presence of at least 1 medical claim with an ICD-9-CM diagnosis code for the condition of interest. Adherence to the index medication was measured by the proportion of days covered (PDC). The PDC was calculated as the ratio of the sum of days supply of all prescription fills during the 12 month followup period divided by 365 days.

Statistical Analysis
Propensity Score Matching. Patients in the BFC and FSC cohorts were propensity score matched to reduce selection bias and create more comparable groups. 20,21 Although adequate clinical information was not available, propensity score matching, using proxies for clinical patient attributes, enabled the formation of comparable cohorts. Random forest methods 22 were used to estimate the propensity scores as the probability of receiving BFC therapy, and patients were matched with the greedy nearest neighbor (1:1) matching technique without replacement. 21 The outcome variable in the model was dichotomous, indicating whether a patient received BFC (1) or FSC (0) therapy. Treatment cohorts were considered well balanced when the P value for the difference between groups was > 0.05 for each of the prespecified variables listed below. The matching scheme specified a priori the balancing of age, sex, prior asthma diagnosis, COPD-related inpatient hospitalizations and ED visits, OCS fills, antibiotic fills, SABA or SABA/SAMA fills, LABA fills, and LAMA fills.
Statistical Models. A generalized linear model (GLM) using the gamma distribution and a log-link function was used to model health care costs. Model adjusted mean differences, 95% confidence intervals, and P values are reported. All costs were adjusted for calendar year and are reported in 2012 dollars. To evaluate utilization outcomes, a GLM with a negative binomial distribution and log link was used for the number of visits and other count data, and logistic models were used for dichotomous outcomes. Adjusted mean differences (AMDs) in costs were calculated as the difference in predicted mean cost values between groups after adjusting for covariates in the statistical model.
Covariates identified in the 12-month pre-index period that remained imbalanced after matching (Table 1) were included in all statistical models, and consisted of the sum of inpatient hospital stays > 5 days (yes vs. no), leukotriene receptor antagonist use (0, 1, ≥ 2 fills), geographic region (Northeast, Midwest, South, or West), peripheral vascular disease/atherosclerosis (yes vs. no), and index-prescribing physician specialty (pulmonologist, internal medicine, family medicine/general practitioner, cardiologist, allergist/immunologist, nonphysician, or other specialty). The models also incorporated the analogous pre-index variable; for example, when modeling post-index allcause health care costs, the model controlled for the pre-index all-cause health care costs. Although P < 0.05 was considered statistically significant for all outcomes, effect estimates and confidence intervals were primarily used in the interpretation of results. No adjustment was made for multiple testing. The propensity scores used for matching were obtained using R, 23 and all other analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC).

■■ Results Cohort Matching
A total of 3,788 BFC and 6,439 FSC initiators met all inclusion/exclusion criteria prior to matching. Following propensity score matching, a total of 3,697 patients from each cohort were included. Table 1 presents the balance of demographics and pre-index variables before and after matching. Descriptive statistics for patients who were and were not matched for each group can be found in the Appendix (available in online article).

Demographic and Clinical Characteristics for Matched Patients
On average, patients were aged 64 years in each treatment group, and the groups had a similar proportion of females (52% BFC and 54% FSC). In addition, there were similar rates of previously diagnosed pneumonia (22% BFC, 23% FSC), asthma (36% BFC, 35% FSC), and hypertension (69% BFC, 68% FSC), among other conditions, during the 12-month pre-index period. Proxies for COPD severity were also well balanced, including the mean number of prior COPD-related inpatient visits (0.13 BFC, 0.14 FSC), COPD-related ED visits (0.18 BFC, 0.19 FSC), and antibiotic fills (2.7 in each group). The use of prior respiratory medications at baseline was also similar for the 2 cohorts, as reflected by proportions of patients with at least 1 fill of OCS (56% BFC, 55% FSC), ICS (12% BFC, 11% FSC), SABA (59% BFC, 60% FSC), and SABA/SAMA combination (23% for both). During the 12-month follow-up period, adherence to the index medication was similar in each group, as evidenced by a PDC of 33% in the BFC cohort and 34% for FSC patients.

Post-index Outcomes
Health Care Utilization. Overall, the rates of COPD-related and all-cause utilization were similar for patients in the 2 cohorts during the 12-month follow-up period, as shown in Table 2. The proportion of patients with COPD-related encounters were similar for the 2 cohorts, including inpatient hospitalizations (6.2% BFC, 6.9% FSC), ICU stays (0.6% and  0, 1, 2+), geographic region, presence of peripheral vascular disease/atherosclerosis, and index prescribing physician specialty (other than pulmonologist) were found to be statistically different between the 2 groups, all of which were controlled for in the multivariable models. b P values compare BFC with FSC and were calculated by using t-tests (age), generalized linear models with Poisson distribution (counts of fills, visits, and exacerbations), and chi-square tests (dichotomous variables). BFC = budesonide/formoterol; COPD = chronic obstructive pulmonary disease; ED = emergency department; FSC = fluticasone/salmeterol; ICS = inhaled corticosteroid; LABA = long-acting beta2-agonist; LAMA = long-acting muscarinic antagonist; OCS = oral corticosteroids; SABA = short-acting beta2-agonist; SAMA = short-acting muscarinic antagonist; SD = standard deviation.

TABLE 1
Propensity Score Matching Results a Health Care Utilization and Costs After Initiating Budesonide/Formoterol Combination or Fluticasone/Salmeterol Combination Among COPD Patients New to ICS/LABA Treatment 0.9%), ED visits (12.3% and 11.8%), and outpatient/office visits (82.4% and 83.1%). No difference was seen in the average length of inpatient hospitalization or the average number of visits for any place of service between the 2 groups.
Pneumonia-related encounters were also similar for patients in the 2 cohorts (    Table 3. Pneumonia-related costs followed a pattern similar to that of COPD-related costs. Patients in the BFC group incurred significantly lower pneumonia-related medical costs compared with patients in the FSC cohort ($2,855 vs. $3,605, AMD = -$716, P < 0.001), which was mainly driven by lower pneumonia-related inpatient costs ($2,728 vs. $3,409, AMD = -$640, P < 0.001).
In all, those initiating BFC incurred lower all-cause health care costs versus FSC patients during the first year after treatment initiation ($21,580 vs. $24,483, AMD = -$1,884, P < 0.001). The difference was driven mainly by lower all-cause inpatient costs ($8,519 vs. $10,314, AMD = -$1,242, P = 0. 012), and lower outpatient/office visit costs ($7,310 vs. $7,921, AMD = -$464, P = 0.006), among BFC versus FSC patients, respectively. the BFC and FSC cohorts, respectively. The average number of visits for each service type and the length of inpatient hospitalization visits were also similar between the 2 groups.

Post-initiation Health Care Costs
Health Care Utilization and Costs After Initiating Budesonide/Formoterol Combination or Fluticasone/Salmeterol Combination Among COPD Patients New to ICS/LABA Treatment patients continue to receive controller medications, the rate at which they require other services, especially costly inpatient hospitalization, could change and impact their overall costs. Although no differences in the number of hospitalizations and other services were detected, small, nonstatistically significant differences, including the length of inpatient hospitalization and prevalence of ICU stays, were seen between the 2 groups. Further evidence, including additional real-world effectiveness studies or randomized trials, is needed to clarify potential additional differences between these 2 agents.
A possible difference in costs may exist if different health plans offer different levels of coverage for the 2 medications being compared. However, in this study it is believed that both drugs, which are of the same class, were covered similarly, and the most recent health plan formularies show no difference in coverage between the 2 medications being studied. [24][25][26] A key strength of this study was the use of a robust design that incorporated propensity score matching to create cohorts with solid bases for comparison over the 12-month follow-up period. Furthermore, the random forest method utilized in the propensity score algorithm has been shown to be more effective in balancing treatment cohorts with less bias than traditional logistic regression techniques. 22 A subset of pneumonia diagnoses in this study was validated via medical chart abstraction and review, which found a positive predictive value of 80%. 19 The other important observation in the study of costs is that COPD-related costs are just a portion of total health care costs, although in this study they accounted for a significant fraction, with more than 20% of all-cause costs related to COPD. Additionally, because the presence of COPD is associated with a number of comorbid conditions, better COPD control may plausibly decrease total health care spending directly and indirectly. Further study is needed to determine whether a strategy of improved ICS/LBA compliance might lead to lower total health care costs while marginally increasing pharmacy costs.

Limitations
The results of this study must be viewed against important limitations, including those associated with a reliance on secondary data. 27,28 They may be generalizable only to commercially insured populations in the United States. Patients were not required to take the index medication during follow-up. As a result, they filled index medication an average of roughly 4 times during follow-up, which resulted in an average of just 33%-34% of post-index days covered with supply of the index medication. Nonetheless, the results of this intent-to-treat analysis were evaluated as the outcomes from the initiation of the study medications without prior ICS/LABA use.
While heavily skewed, as cost data tend to be, differences in total all-cause costs were not influenced by outliers. The BFC group had the only observation that could be considered an outlier, with a cost more than triple the amount of the next highest cost in the cohort, whereas the FSC group had no such outliers. COPD-related costs contained no major outliers, whereas pneumonia-related costs had 1 large outlier in the BFC group with a value of more than 3 times greater than the second highest cost, and the FSC group had 1 moderate outlier with a cost more than 75% higher than the next highest.

■■ Discussion
In this study, well-balanced cohorts of COPD patients receiving BFC or FSC treatments had similar all-cause, COPD-related, and pneumonia-related utilization rates for inpatient hospitalizations, ED visits, and outpatient/office visits. There were, however, statistically significant differences in all-cause, COPDrelated, and pneumonia-related costs, reflecting the cumulative effect of the marginal differences between each utilization category. Overall, patients receiving BFC incurred lower COPDrelated costs relative to patients receiving FSC therapy because of lower mean inpatient hospitalization, pharmacy, and outpatient/office visit costs, which more than offset the slightly higher per patient ED visit costs. This trend was repeated for all-cause costs driven by lower inpatient costs and lower outpatient/office visit costs incurred by BFC patients relative to the FSC cohort. Lower mean pneumonia-related inpatient costs among patients in the BFC cohort were the main contributor to the overall lower pneumonia-related costs relative to the FSC group. Although no statistical differences were found for measures of health care utilization, the FSC cohort had more patients with an ICU stay (6.5% vs. 6.0%) and had longer inpatients lengths of stay on average (mean days: 11.2 vs. 9.3), both of which are associated with high costs; thus, small nonstatistical differences in their utilization may be responsible for statistically significant differences in overall health care costs.
In contrast to these findings, a study by Roberts et al. (2011) reported no significant differences in COPD-related costs for medical services during the 3-to 6-month follow-up period. 4 The authors reported that pharmacy costs were $43 greater for FSC relative to BFC patients during the limited follow-up period (compared with $121 over a 12-month follow-up in this study), which were attributed to the greater mean medication possession ratio among patients receiving FSC treatment. 4 However, in the current study, adherence to the index medication, as measured by the PDC, was similar between the 2 groups. The Roberts et al. study was similar to our study in a number of key respects: patients were health plan enrollees, and sample size and age and sex distributions were generally similar. However, the difference in follow-up time, 6 months versus 1 year, was a salient difference. 4 Although evidence from prior studies is not currently available, it is not implausible that as COPD There was a lack of detailed clinical information, including smoking status, pulmonary function assessment, and patient reported outcomes, to adjust for COPD disease severity and activity or to confirm COPD diagnoses, because such information is absent from the primary data source, administrative claims. However, the study matched on prior COPD exacerbations, which is the best predictor of future exacerbations. 8 Pharmacy medications administered during inpatient hospitalizations were not included because that information was not available in these data. It was not possible to determine the primary reason for outpatient and ED visits via claims data; as a result, even when a COPD diagnosis code was present, the visit might have been for routine follow-up or non-COPDrelated reasons. 29 Thus, the results of this study might not be generalized to BFC or FSC users with COPD overall.

■■ Conclusions
No difference was found in rates of health care utilization between the 2 groups; however, this study demonstrated an association between COPD patients initiating BFC therapy and lower COPD-related costs relative to patients initiating FSC treatment. This result represented the cumulative effect of lower mean costs for inpatient hospitalizations, pharmacy, and outpatient/office visits counterbalancing slightly higher average ED visit costs. BFC patients also had lower all-cause costs, which were driven by lower hospitalization and outpatient/ office visit costs incurred by BFC versus FSC patients, and a similar trend was observed for pneumonia-related costs. This is the first study comparing resource utilization and costs of BFC and FSC administered to ICS/LABA-naïve patients for a full year following treatment initiation. Additional studies are needed to evaluate other key aspects of the economic outcomes of BFC and FSC use among COPD patients.